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Ror family receptor tyrosine kinases regulate the maintenance of neural progenitor cells in the developing neocortex

Mitsuharu Endo1, Ryosuke Doi, Michiru Nishita

  • 1Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan.

Journal of Cell Science
|February 14, 2012
PubMed

Insights

The Wnt5a-Ror1 and Wnt5a-Ror2 signaling pathways maintain neural progenitor cells (NPCs) in the developing neocortex. This signaling is crucial for regulating neurogenesis and NPC proliferation during brain development.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Cell Signaling

Background:

  • Receptor tyrosine kinases (RTKs) Ror1 and Ror2, along with Wnt5a, are implicated in developmental processes.
  • Their specific roles in mammalian neural development, particularly in the neocortex, remain largely uncharacterized.
  • Neural progenitor cells (NPCs) are critical for generating neurons during brain development.

Purpose of the Study:

  • To investigate the role of Wnt5a-Ror1 and Wnt5a-Ror2 signaling in neocortical neural progenitor cells (NPCs).
  • To elucidate the molecular mechanisms by which these pathways regulate neurogenesis and NPC maintenance.
  • To determine the involvement of Dishevelled 2 (Dvl2) in this signaling cascade.

Main Methods:

  • siRNA-mediated knockdown of Ror1, Ror2, and Wnt5a in cultured embryonic neocortical NPCs.
  • Immunohistochemical analysis for neuronal markers (βIII-tubulin), intermediate progenitor markers (Tbr2), NPC markers (Pax6), and glial markers (GFAP).
  • BrdU-labeling experiments to assess NPC proliferation and neurogenesis.
  • Analysis of Dvl2 involvement in Wnt5a-Ror signaling.

Main Results:

  • Knockdown of Ror1, Ror2, or Wnt5a reduced βIII-tubulin-positive neuron production from NPCs, potentially via Tbr2-positive progenitors.
  • Suppression of these molecules decreased the proportion of proliferative and neurogenic NPCs (Pax6-positive, GFAP-negative).
  • Wnt5a-Ror signaling in NPCs involves Dvl2, and its suppression also reduced NPC proliferation and neurogenesis.
  • Knockdown of Ror1 or Ror2 led to precocious NPC differentiation into neurons, while forced expression delayed differentiation.

Conclusions:

  • Wnt5a-Ror1 and Wnt5a-Ror2 signaling pathways are essential for maintaining proliferative and neurogenic NPCs in the developing neocortex.
  • These pathways regulate neurogenesis by controlling NPC maintenance and differentiation timing.
  • Dvl2 is a key mediator in the Wnt5a-Ror signaling pathway within NPCs.

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